Éditeur(s) : HAL CCSD American Society of Tropical Medicine and Hygiene
Résumé : International audience
Anti-leishmaniasis drug resistance is a common problem worldwide. The aim of this study was to inventory the general in vitro level of sensitivity of Leishmania isolates circulating in French Guiana and to highlight potential in vitro pentamidine-resistant isolates. This sensitivity study was conducted on 36 patient-promastigote isolates for seven drugs (amphotericin B, azithromycin, fluconazole, meglumine antimoniate, miltefosine, paromomycin, and pentamidine) using the Cell Counting Kit-8 viability test. The IC50 values obtained were heterogeneous. One isolate exhibited high IC50 values for almost all drugs tested. Pentamidine, which is the first-line treatment in French Guiana, showed efficacy at very low doses (mean of 0.0038 μg/mL). The concordance of the in vitro pentamidine results with the patients' clinical outcomes was 94% (K = 0.82).
ISSN: 0002-9637

inserm-01481512
http://www.hal.inserm.fr/inserm-01481512
http://www.hal.inserm.fr/inserm-01481512/document
http://www.hal.inserm.fr/inserm-01481512/file/2017%2C%20Ginouves%20-%20In%20vitro%20sensitivity%20of%20cutaneous%20leishmania.pdf
DOI : 10.4269/ajtmh.16-0373

Éditeur(s) : HAL CCSD Oxford University Press (OUP): Policy B1 - Oxford Open Option B Oxford University Press (OUP)
Résumé : International audience
BACKGROUNDA very large proportion of the literature on the endocrine disruptors categorized as anti-androgens deals with phthalates, which are produced in large amounts for use as plastic emollients and additives. In this review, we bring together and analyse work on the effects of phthalates in animals and humans at different stages of their development to assess whether or not their possible anti-androgenic properties represent a significant threat to human health.METHODSThe database PubMed was systematically searched for all English language articles until July 2013 in each subject area discussed.RESULTSWe provide an up-to-date exhaustive, comparative and critical assessment of both in vivo and in vitro studies undertaken to explore the effects of phthalates on the human testis from fetal life to adulthood. These results are compared and discussed in the light of the key data reported in the literature for mice and rats.CONCLUSIONSThe current literature highlights the fact that (i) there is a huge difference between the number of studies performed in animals and in humans, with many fewer for humans; (ii) there are differences in the way rats, mice, primates and humans respond to phthalates, for reasons that need to be further explored; (iii) more work is required to clarify the contradictions, in the few existing human epidemiological studies at all stages of development, which may be partly explained by varying methods of exposure assessment; (iv) in accordance with recent findings in rodents, it cannot be excluded that transgenerational effects of phthalates and/or epigenetic changes exist in humans; (v) a number of methodological limitations need to be solved for the in vitro and xenografting models using human fetal testis to fulfil their 'missing link' role between epidemiological studies in humans and rodent models; and (vi) epidemiological and in vitro studies generally converge sufficiently to conclude that phthalate anti-androgenicity is plausible in adult men.
ISSN: 1355-4786

inserm-00869540
http://www.hal.inserm.fr/inserm-00869540
DOI : 10.1093/humupd/dmt050
PUBMED : 24077978

Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
Aim of the study: A knowledge attitude and practice study centred on leishmaniasis and its treatment was performed among the Chayahuita, an Amazonian Peruvian ethnic group living in an endemic area. This study documents traditional Chayahuita plant's use and disease concepts. Also, activty of some medicinal plants used by the Chayahuita is highlighted and discussed. Materials and methods: Ninety-three Chayahuita people were interviewed, following a semi-structured questionnaire focussed on disease knowledge and perception, personal attitude and healing practices. Simultaneously, a collection of plants was performed in different ecotopes, in order to make an extensive inventory of the pharmacopoeia. Results: For the Chayahuita, cutaneous (CL) and muco-cutaneous leishmaniasis (MCL) are considered as diseases of their own, with specific names, aetiologies, mode of transmission. Regarding CL, Chayahuita people consider that the humid characteristic of the skin ulcer is a discriminative fact orienting the diagnostic forTa'ta' (leishmaniasis). Forty-six different species were designated useful against LC and /or MCL (29 species by means of the questionnaire and 27 species when collecting in different ecotopes). Thirty-seven extracts corresponding to 31 species used medicinally were screened in vitro against Leishmania amnzonensis axenic amastigotes, assessing their viability by the reduction of tetrazolium salt (MTT). Six species displayed a good activity ( 10 μg/ml < IC50 < 20 μg/ml): an undetermined hemi-epiphytic Clusiaceae, Cyhianthus anthuriophyllus Pipoly (Myrsinaceae), two Piper, Piper sanguineispicum Trel., and Piper loretoanum Trel. (Piperaceae), Desmodium axillare Sw. DC. (Fabaceae), and Clibadium sylvestre (Aubl.) Baill. (Asteraceae). Conclusion: Perception of leishmaniasis, attitude, treatments and diet prohibitions still largely reflects traditional Chayahuita cosmovision, even if some tentative of bio-medical re-interpretation is arising.
ISSN: 0378-8741

hal-01087667
https://hal-agroparistech.archives-ouvertes.fr/hal-01087667
DOI : 10.1016/j.jep.2009.07.015

Éditeur(s) : Edp Sciences S A
Résumé : Sperm characteristics of scallops have not been well described in the scientific literature. The effects of sperm release technique (thermal shock versus serotonin injection), of sperm collection technique (testis sampling versus serotonin injection), of sperm sampling location along the genital tract, of in vitro sperm maturation, and of time post activation on scallop sperm characteristics were assessed in the present work. Whatever sperm release technique used, no significant differences were observed regarding the percentage of motile spermatozoa and the velocity of the average path (YAP). Compared to testicular sperm, a higher percentage of motile spermatozoa, YAP and intracellular adenosine triphosphate (ATP) content were observed for sperm shed after serotonin injection. From the distal part of testes up to the gonopore, an increase of the percentage of motile spermatozoa and YAP was assessed, suggesting a sperm 'maturation process' along the genital ducts. A higher increase in the percentage of motile sperm was recorded during a 5 mm incubation of testicular sperm in seawater containing 2 mM serotonin and seawater containing 10 mM caffein compared to seawater (control). In addition, a higher YAP was assessed, incubating testicular sperm in caffein, compared to control or serotonin. Then, the percentage of motile spermatozoa, YAP and intracellular ATP content exhibited a progressive reduction during the 10 h swimming period. Mean values of the percentage of motile spermatozoa, YAP, sperm track linearity (LIN) and intracellular ATP content recorded at the beginning of the movement period for sperm samples collected after intragonadal serotonin injection, were 82 +/- 7%, 162 +/- 15 mu m s(-1), 0.33 +/- 0.12 and 212 +/- 133 nmol x 10(-9) spermatozoa (n = 9 males), respectively. The present study confirms the existence of a sperm "maturation process" along scallop genital ducts. In addition, the cessation of scallop sperm movement can be explained by the exhaustion of ATP content at the end of the movement phase.
Aquatic Living Resources (0990-7440) (Edp Sciences S A), 2013-07 , Vol. 26 , N. 3 , P. 215-220

Droits : EDP Sciences, IFREMER, IRD 2013
http://archimer.ifremer.fr/doc/00157/26852/24983.pdf
DOI:10.1051/alr/2013048
http://archimer.ifremer.fr/doc/00157/26852/

Éditeur(s) : HAL CCSD Institute of Electrical and Electronics Engineers
Résumé : International audience
: A new set-up for exposure of human cells in vitro at 37°C to pulse-modulated 300 MHz and 500 MHz signals of future magnetic resonance imaging (MRI) systems is designed, built up, and characterized. Two dipole antennas, specifically designed for ultra high field MRI, are used as radiating structures. The electromagnetic (EM) field distribution inside the incubator containing the cells is computed, and it is shown to be in a good agreement with measurements. The electric field at the cell level is quantified numerically. Local, 1g average, and averaged over the culture medium volume SAR are provided along with the standard deviation values for each well. Temperature increments are measured inside the culture medium during the exposure using an optical fiber thermometer. Then we identify the pulse parameters corresponding to the thermal threshold of 1°C, usually considered as a threshold for thermally-induced biological effects. For these parameters, the induction of heat shock proteins is assessed to biologically verify a potential thermal response of cells. The data demonstrate that, under the considered experimental conditions, exposure to pulsemodulated radiations emulating typical ultra high field MRI signals, corresponding to temperature increments below 1°C, does not trigger any heat shock response in human brain cells.
ISSN: 0018-9294

hal-00874329
https://hal.archives-ouvertes.fr/hal-00874329
DOI : 10.1109/TBME.2013.2270371
PUBMED : 23799680

Éditeur(s) : HAL CCSD
Résumé : International audience
A prospective study on randomized patients was conducted to determine how morphokinetic parameters are altered in embryos grown in sequential versus global culture media. Eleven morphokinetic parameters of 160 single embryos transferred were analyzed by time lapse imaging involving two University-affiliated in vitro fertilization (IVF) centers. We found that the fading of the two pronuclei occurred earlier in global (22.56±2.15 hpi) versus sequential media (23.63±2.71 hpi; p=0.0297). Likewise, the first cleavage started earlier at 24.52±2.33 hpi vs 25.76±2.95 hpi (p=0.0158). Also, the first cytokinesis was shorter in global medium, lasting 18±10.2 minutes in global versus 36±37.8 minutes in sequential culture medium (p <0.0001). We also observed a significant shortening in the duration of the 2-cell stage in sequential medium: 10.64 h±2.75 versus 11.66 h±1.11 in global medium (p=0.0225) which suggested a faster progression of the embryos through their first mitotic cell cycle. In conclusion, morphokinetic analysis of human embryos by Time lapse imaging reveals significant differences in five kinetic variables according to culture medium. Our study highlights the need to adapt morphokinetic analysis accordingly to the type of media used to best support human early embryo development.
Annales de Biologie Clinique

hal-01579406
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01579406
DOI : 10.1684/abc.2017.1259
PUBMED : 28751285

Éditeur(s) : HAL CCSD Oxford University Press (OUP)
Résumé : International audience
STUDY QUESTION: Do mild analgesics affect the endocrine system of the human adult testis? SUMMARY ANSWER: Mild analgesics induce multiple endocrine disturbances in the human adult testis in vitro. WHAT IS KNOWN ALREADY: Mild analgesics have recently been incriminated as potential endocrine disruptors. Studies of the effects of these widely used molecules on the androgenic status of men are limited and somewhat contradictory. This prompted us to investigate whether these compounds could alter the adult human testicular function. We therefore assessed in parallel the effects of paracetamol, aspirin and indomethacin on organo-cultured adult human testis and on the NCI-H295R steroid-producing human cell line. STUDY DESIGN, SIZE, DURATION: Adult human testis explants or NCI-H295R adrenocortical human cells were cultured with 10(-4) or 10(-5) M paracetamol, aspirin or indomethacin for 24-48 h. The effect of 10(-5) M ketoconazole, used as an anti-androgenic reference molecule, was also assessed. PARTICIPANTS/MATERIALS, SETTING, METHODS: Testes were obtained from prostate cancer patients, who had not received any hormone therapy. The protocol was approved by the local ethics committee of Rennes, France and informed consent was given by the donors. Only testes displaying spermatogenesis, as assessed by transillumination, were used in this study. Hormone levels in the culture media were determined by radioimmunoassay (testosterone, insulin-like factor 3), Enzyme-Linked Immunosorbent Assay (inhibin B) or Enzyme Immunosorbent Assay [prostaglandin (PG) D2, and PGE2]. Tissues were observed and cells counted using classical immunohistochemical methods. MAIN RESULTS AND THE ROLE OF CHANCE: The three mild analgesics caused multiple endocrine disturbances in the adult human testis. This was particularly apparent in the interstitial compartment. Effective doses were in the same range as those measured in blood plasma following standard analgesic treatment. The production of testosterone and insulin-like factor 3 by Leydig cells was altered by exposure to all these drugs. Inhibin B production by Sertoli cells was marginally affected by aspirin only. Our experiments also revealed that mild analgesics display direct anti-PG activity, which varied depending on the drug used, the dose and the duration of exposure. Nevertheless, associations between the alteration of the PG and testosterone profiles were not systematically observed, suggesting that a combination of mechanisms of endocrine disruption is at play. LIMITATIONS, REASONS FOR CAUTION: Our studies were performed in vitro. WIDER IMPLICATIONS OF THE FINDINGS: We provide the first evidence that direct exposure to mild analgesics can result in multiple endocrine disturbances in the human adult testis. Caution, concerning the consumption of mild analgesics by men, should be strengthened, particularly in high-risk population subgroups such as elite athletes.
ISSN: 0268-1161

inserm-00866016
http://www.hal.inserm.fr/inserm-00866016
PUBMED : 23670170
DOI : 10.1093/humrep/det112

Éditeur(s) : HAL CCSD Institute of Electrical and Electronics Engineers
Résumé : International audience
An effective solution for increasing the exposure uniformity and efficiency of biological samples in in vitro bioelectromagnetic experiments at 60 GHz is proposed by introducing a novel choke ring antenna (CRA). The CRA is optimized to provide a uniform exposure of samples, whose dimensions are equivalent to those of a standard 35-mm Petri dish, positioned close to the antenna aperture, i.e., 10-20 wavelengths. The antenna prototype is fabricated in metallized foam. The realized exposure efficiency of the sample exceeds 55% (if estimated for an exposure uniformity better than - 0.5 dB). To validate the numerical results, the field intensity profiles on the surface of a high-water-content phantom have been experimentally obtained using a high-resolution infrared camera. Compared to the standard open-ended waveguide and horn antennas, typically used for millimeter-wave dosimetry, a twofold advantage of the proposed CRA is demonstrated, namely, the improvement of the exposure efficiency by a factor of 1.5 to 2 with a simultaneous reduction of the exposure distance by a factor of 8-2, respectively, depending on the type of the reference antenna. These advantages make the proposed CRA an excellent candidate for 60-GHz short-range exposure systems for in vitro bioelectromagnetic studies.
ISSN: 0018-9480

hal-00874349
https://hal.archives-ouvertes.fr/hal-00874349
DOI : 10.1109/TMTT.2013.2255619

Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
Primary hepatocyte cultures are now considered as convenient models for in vitro analyzing liver drug transport. However, if primary human and rat hepatocytes have been well-characterized with respect to drug transporter expression and regulation, much less is known for primary mouse hepatocytes. The present study was therefore designed to gain insights about this point. The profile of sinusoidal and canalicular drug transporter mRNA expression in short time (4h)-cultured mouse hepatocytes was found to be highly correlated with that of freshly isolated hepatocytes; by contrast, those of counterparts cultured for a longer time (until 4days) either in monolayer configurations on plastic or collagen or in sandwich configuration with matrigel were profoundly altered: uptake drug transporters such as Oct1, Oatps and Oat2 were thus down-regulated, whereas most of efflux transporters such as Mdr1a/b, Mrp3, Mrp4 and Bcrp were induced. Moreover, short time-cultured hepatocytes exhibited the highest levels of sinusoidal influx transporter activities. Transporter-mediated drug secretion into canalicular networks was however only observed in sandwich-cultured hepatocytes. Mouse hepatocytes cultured either in monolayer or sandwich configurations were finally shown to exhibit up-regulation of referent transporters in response to exposure to prototypical activators of the drug sensing receptors pregnane X receptor, aryl hydrocarbon receptor or constitutive androstane receptor. Taken together, these data demonstrate the feasibility of using primary mouse hepatocytes for investigating potential interactions of xenobiotics with hepatic transporter activity or regulation, provided that adequate culture conditions are retained.
ISSN: 0928-0987

inserm-00823243
http://www.hal.inserm.fr/inserm-00823243
DOI : 10.1016/j.ejps.2013.01.013
PUBMED : 23396053

Éditeur(s) : HAL CCSD American Chemical Society
Résumé : International audience
The HIWATE (Health Impacts of long-term exposure to disinfection byproducts in drinking WATEr) project was a systematic analysis that combined the epidemiology on adverse pregnancy outcomes and other health effects with long-term exposure to low levels of drinking water disinfection byproducts (DBPs) in the European Union. The present study focused on the relationship of the occurrence and concentration of DBPs with in vitro mammalian cell toxicity. Eleven drinking water samples were collected from five European countries. Each sampling location corresponded with an epidemiological study for the HIWATE program. Over 90 DBPs were identified; the range in the number of DBPs and their levels reflected the diverse collection sites, different disinfection processes, and the different characteristics of the source waters. For each sampling site, chronic mammalian cell cytotoxicity correlated highly with the numbers of DBPs identified and the levels of DBP chemical classes. Although there was a clear difference in the genotoxic responses among the drinking waters, these data did not correlate as well with the chemical analyses. Thus, the agents responsible for the genomic DNA damage observed in the HIWATE samples may be due to unresolved associations of combinations of identified DBPs, unknown emerging DBPs that were not identified, or other toxic water contaminants. This study represents the first to integrate quantitative in vitro toxicological data with analytical chemistry and human epidemiologic outcomes for drinking water DBPs.
ISSN: 0013-936X

hal-00875923
https://hal.archives-ouvertes.fr/hal-00875923
DOI : 10.1021/es3024226
PUBMED : 22958121

Éditeur(s) : HAL CCSD American Association for Cancer Research
Résumé : International audience
The aim of this study was to test in vitro the efficacy of TAC, an original G-quadruplex ligand, as a potential radiosensitizing agent for glioblastoma multiforme (GBM). Two human radioresistant telomerase-positive GBM cell lines (SF763 and SF767) were analyzed, with and without TAC treatment, for telomere length, cell proliferation, apoptosis, cell-cycle distribution, gene expression, cytogenetic aberrations, clonogenic survival assay, 53BP1 immunofluorescence staining, and γH2AX phosphorylation. We found that low concentrations of TAC (0.5 and 1 μmol/L) inhibited the proliferation of GBM cells in a concentration-dependent manner after only 1 week of treatment, with minimal effects on cell cycle and apoptosis. TAC treatment had no visible effect on average telomere length but modified expression levels of telomere-related genes (hTERT, TRF1, and TRF2) and induced concentration-dependent DNA damage response and dicentric chromosomes. Survival curves analysis showed that exposure to nontoxic, subapoptotic concentrations of TAC enhanced radiation-induced killing of GBM cells. Analysis of DNA repair after irradiation revealed delayed repair kinetics in GBM cells treated with TAC. Furthermore, the combined treatment (TAC and radiation) significantly increased the frequency of chromosomal aberrations as compared with radiation alone. These findings provide the first evidence that exposure to a G4 ligand radiosensitizes human glioblastoma cells and suggest the prospect of future therapeutic applications.
ISSN: 1535-7163

hal-00851184
https://hal.archives-ouvertes.fr/hal-00851184
DOI : 10.1158/1535-7163.MCT-10-0664
PUBMED : 21987532

Éditeur(s) : HAL CCSD Society for the Study of Reproduction
Résumé : International audience
Transcription factor GATA4 is required for the development and function of the mammalian gonads. We first reported that the GATA4 gene in both human and rodents is expressed as two major alternative transcripts that differ solely in their first untranslated exon (exon 1a vs. exon 1b). We had also showed by quantitative PCR that in mouse tissues, both Gata4 exon 1a- and 1b-containing transcripts are present in all sites that are normally positive for GATA4 protein. In adult tissues, exon 1a-containing transcripts generally predominate. A notable exception, however, is the testis where the Gata4 exon 1a and 1b transcripts exhibit a similar level of expression. We now confirm by in situ hybridization analysis that each transcript is also strongly expressed during gonad differentiation in both sexes in the rat. To gain further insights into how Gata4 gene expression is controlled, we characterized the mouse Gata4 promoter sequence located upstream of exon 1b. In vitro studies revealed that the Gata4 1b promoter is less active than the 1a promoter in several gonadal cell lines tested. Whereas we have previously shown that endogenous Gata4 transcription driven by the 1a promoter is dependent on a proximally located Ebox motif, we now show using complementary in vitro and in vivo approaches that Gata4 promoter 1b-directed expression is regulated by GATA4 itself. Thus, Gata4 transcription in the gonads and other tissues is ensured by distinct promoters that are regulated differentially and independently.
ISSN: 0006-3363

hal-01010626
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01010626
DOI : 10.1095/biolreprod.113.113290
PUBMED : 24352556

Éditeur(s) : HAL CCSD
Résumé : International audience
In vitro evaluation of P-glycoprotein (P-gp) inhibitory potential is now a regulatory issue during drug development, in order to predict clinical inhibition of P-gp and subsequent drug-drug interactions. Assays for this purpose, commonly based on P-gp-expressing cell lines and digoxin as a reference P-gp substrate probe, unfortunately exhibit high variability, raising thus the question of developing alternative or complementary tests for measuring inhibition of P-gp activity. In this context, the present study was designed to investigate the use of the fluorescent dye rhodamine 123 as a reference P-gp substrate probe for characterizing P-gp inhibitory potential of 16 structurally-unrelated drugs known to interact with P-gp. 14/16 of these P-gp inhibitors were found to increase rhodamine 123 accumulation in P-gp-overexpressing MCF7R cells, thus allowing the determination of their P-gp inhibitory potential, i.e., their half maximal inhibitor concentration (IC50) value towards P-gp-mediated transport of the dye. These IC50 values were in the range of variability of previously reported IC50 for P-gp and can be used for the prediction of clinical P-gp inhibition according to Food and Drug Administration (FDA) criteria, with notable sensitivity (80%). Therefore, the data demonstrated the feasibility of the use of rhodamine 123 for evaluating the P-gp inhibitory potential of drugs
Pharmaceutics

hal-01305488
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01305488
DOI : 10.3390/pharmaceutics8020012
PUBMED : 27077878

Éditeur(s) : HAL CCSD Springer Verlag
Résumé : International audience
Chlordecone (Kepone) is an organochlorine insecticide that has been used as insecticide and fungicide. In the French West Indies, Guadeloupe and Martinique, it was intensively applied to banana fields from 1973 to 1993 to control root borers. This pesticide undergoes no significant biotic or abiotic degradation in the environment and is still present in soils where it was applied. It was only in 1999 that health and environmental authorities became aware of the extent of the chlordecone pollution of environmental media, including soils, waterways, and the food chain. Earlier observations and toxicological studies have demonstrated that chlordecone is a reproductive and developmental toxicant, neurotoxic and carcinogenic in rodents, and is an endocrine-disrupting chemical because of its estrogenic properties both in vitro and in vivo. Several surveys have confirmed that the French West Indian population continues to be exposed to this chemical though consumption of contaminated foodstuffs. Here, we report the findings of various epidemiological studies conducted in the French West Indies to assess the impact of environmental exposure to chlordecone on the health of the population.
ISSN: 0944-1344

hal-01150382
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01150382
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01150382/document
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01150382/file/Chlordecone%20exposure%20and%20adverse%20effects%20in%20French%20West.pdf
DOI : 10.1007/s11356-015-4621-5

Éditeur(s) : HAL CCSD Springer Verlag
Résumé : International audience
The implication of oxidative stress as primary mechanism inducing doxorubicin (DOX) cardiotoxicity is still questionable as many in vitro studies implied supra-clinical drug doses or unreliable methodologies for reactive oxygen species (ROS) detection. The aim of this study was to clarify whether oxidative stress is involved in compliance with the conditions of clinical use of DOX, and using reliable tools for ROS detection. We examined the cytotoxic mechanisms of 2 μM DOX 1 day after the beginning of the treatment in differentiated H9c2 rat embryonic cardiac cells. Cells were exposed for 2 or 24 h with DOX to mimic a single chronic dosage or to favor accumulation, respectively. We found that apoptosis was prevalent in cells exposed for a short period with DOX: cells showed typical hallmarks as loss of anchorage ability, mitochondrial hyperpolarization followed by the collapse of mitochondrial activity, and nuclear condensation. Increasing the exposure period favored a shift to necrosis as the cells preferentially exhibited early DNA impairment and nuclear swelling. In either case, measuring the fluorescence lifetime of 1-pyrenebutyric acid or the intensities of dihydroethidium or amplex red showed a consistent pattern in ROS production which was a slight increased level far from representative of an oxidative stress. Moreover, pre-treatment with dexrazoxane provided a cytoprotective effect although it failed to detoxify ROS. Our data support that oxidative stress is unlikely to be the primary mechanism of DOX cardiac toxicity in vitro.
ISSN: 0300-8177

hal-01285736
https://hal-univ-perp.archives-ouvertes.fr/hal-01285736
DOI : 10.1007/s11010-016-2653-x

Éditeur(s) : HAL CCSD
Résumé : International audience
We have previously shown that primary rat hepatocyte treatment by n-3 polyunsaturated fatty acids (omega 3) gave opposite results concerning early ethanol cytotoxicity (only a 5-hours-intoxication period) depending on the tested omega 3 type. The aim of this study was to follow on experiments in other in vitro and in vivo models that allowed longer intoxication times with ethanol. When highly differentiated hepatocytes from WIF-B9 line were treated with ethanol for 4 days, docosahexaenoic acid (DHA) protected from ethanol-induced cell death and oxidative stress, whereas eicosapentaenoic acid (EPA) increased ethanol toxic effects. In vivo, Zebrafish larvae exhibited a similar behavior after 7 days of ethanol intoxication depending on the omega 3 introduced in the bath. Altogether, these data confirm differential effects for omega 3s even for longer exposure times with ethanol.
Cahiers de l'Ireb

hal-01117633
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01117633

Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
Endocrine disrupting chemicals and especially oestrogen receptor (ER) agonists have been extensively studied over the years due to their potential effects on sexual development and reproduction in vertebrates, notably fish. As ER agonists can exist as complex mixtures in the aquatic environment, evaluating the impact of combined exposure on oestrogenic effects has become increasingly important. Use of predictive models such as concentration addition (CA) and independent action (IA) has allowed assessment of combined estrogenic effects of complex multi-compound mixtures of ER agonists in various fish in vitro and in vivo experimental models. The present work makes use of a transgenic zebrafish strain, tg(cyp19a1b-GFP), which expresses the green fluorescent protein (GFP) under the control of the cyp19a1b (brain aromatase or aromatase B) gene to determine the oestrogenic potency of ER agonists alone or in mixtures. In these studies, tg(cyp19a1b-GFP) zebrafish embryos were exposed for four days (from one to five days post fertilization) to five different oestrogenic chemicals; 17α-ethinylestradiol (EE2), 17β-estradiol (E2), estrone (E1), bisphenol A (BPA) and 4-tert-octylphenol (OP), and three mixtures of up to four of these compounds. The mixture of BPA, OP and E2 was also tested with primary cultures of rainbow trout hepatocytes by analysing the ER-mediated induction of the oestrogenic biomarker vitellogenin in order to compare the performance of the two methods for assessing oestrogenic effects of complex mixtures. The three tested mixtures were predominantly acting in an additive manner on the expression of GFP. Additivity was indicated by the overlap of the 95% confidence interval of the concentration response curves for the observed data with the CA and IA prediction models, and model deviation ratios within a factor of two for a majority of the mixture concentrations. However, minor deviations determined as more than additive effects for the mixture of EE2, E1 and E2 and less than additive effects for the mixture of BPA, OP, EE2 and E1 were observed at the higher mixture concentrations tested. The successful prediction of additivity by CA and IA in tg(cyp19a1b-GFP) zebrafish embryos and deviations at high mixture concentrations seemed to correspond well to results obtained in the rainbow trout hepatocyte assay. The present results clearly show the usefulness of combining predictive modelling and use of in vitro bioassays for rapid screening of oestrogenic effects of complex mixtures and environmental samples.
ISSN: 0166-445X

hal-00877351
https://hal.archives-ouvertes.fr/hal-00877351
DOI : 10.1016/j.aquatox.2013.05.001
PUBMED : 23721851

Éditeur(s) : HAL CCSD
Résumé : International audience
Estrogen receptor alpha (ERα) has been recognized now for several decades as playing a key role in reproduction and exerting functions in numerous nonreproductive tissues. In this review, we attempt to summarize the in vitro studies that are the basis of our current understanding of the mechanisms of action of ERα as a nuclear receptor and the key roles played by its two activation functions (AFs) in its transcriptional activities. We then depict the consequences of the selective inactivation of these AFs in mouse models, focusing on the prominent roles played by ERα in the reproductive tract and in the vascular system. Evidence has accumulated over the two last decades that ERα is also associated with the plasma membrane and activates non-nuclear signaling from this site. These rapid/nongenomic/membrane-initiated steroid signals (MISS) have been characterized in a variety of cell lines, and in particular in endothelial cells. The development of selective pharmacological tools that specifically activate MISS and the generation of mice expressing an ERα protein impeded for membrane localization have begun to unravel the physiological role of MISS in vivo. Finally, we discuss novel perspectives for the design of tissue-selective ER modulators based on the integration of the physiological and pathophysiological roles of MISS actions of estrogens.
Physiological Reviews

hal-01533249
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01533249
DOI : 10.1152/physrev.00024.2016
PUBMED : 28539435

Éditeur(s) : HAL CCSD Public Library of Science
Résumé : International audience
Two of the crucial aspects of human immunodeficiency virus (HIV) infection are (i) viral persistence in reservoirs (precluding viral eradication) and (ii) chronic inflammation (directly associated with all-cause morbidities in antiretroviral therapy (ART)-controlled HIV-infected patients). The objective of the present study was to assess the potential involvement of adipose tissue in these two aspects. Adipose tissue is composed of adipocytes and the stromal vascular fraction (SVF); the latter comprises immune cells such as CD4+ T cells and macrophages (both of which are important target cells for HIV). The inflammatory potential of adipose tissue has been extensively described in the context of obesity. During HIV infection, the inflammatory profile of adipose tissue has been revealed by the occurrence of lipodystrophies (primarily related to ART). Data on the impact of HIV on the SVF (especially in individuals not receiving ART) are scarce. We first analyzed the impact of simian immunodeficiency virus (SIV) infection on abdominal subcutaneous and visceral adipose tissues in SIVmac251 infected macaques and found that both adipocytes and adipose tissue immune cells were affected. The adipocyte density was elevated, and adipose tissue immune cells presented enhanced immune activation and/or inflammatory profiles. We detected cell-associated SIV DNA and RNA in the SVF and in sorted CD4+ T cells and macrophages from adipose tissue. We demonstrated that SVF cells (including CD4+ T cells) are infected in ART-controlled HIV-infected patients. Importantly, the production of HIV RNA was detected by in situ hybridization, and after the in vitro reactivation of sorted CD4+ T cells from adipose tissue. We thus identified adipose tissue as a crucial cofactor in both viral persistence and chronic immune activation/inflammation during HIV infection. These observations open up new therapeutic strategies for limiting the size of the viral reservoir and decreasing low-grade chronic inflammation via the modulation of adipose tissue-related pathways
ISSN: 1553-7366

Droits : http://creativecommons.org/licenses/by/
hal-01207287
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01207287
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01207287/document
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01207287/file/journal.ppat.1005153.pdf
DOI : 10.1371/journal.ppat.1005153

Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
Experimental studies have demonstrated that the antileukemic trivalent inorganic arsenic prevents the development of severe pro-inflammatory diseases mediated by excessive Th1 and Th17 cell responses. Differentiation of Th1 and Th17 subsets is mainly regulated by interleukins (ILs) secreted from dendritic cells (DCs) and the ability of inorganic arsenic to impair interferon-γ and IL-17 secretion by interfering with the physiology of DCs is unknown. In the present study, we demonstrate that high concentrations of sodium arsenite (As(III), 1-2 μM) clinically achievable in plasma of arsenic-treated patients, block differentiation of human peripheral blood monocytes into immature DCs (iDCs) by inducing their necrosis. Differentiation of monocytes in the presence of non-cytotoxic concentrations of As(III) (0.1 to 0.5 μM) only slightly impacts endocytotic activity of iDCs or expression of co-stimulatory molecules in cells activated with lipopolysaccharide. However, this differentiation in the presence of As(III) strongly represses secretion of IL-12p70 and IL-23, two major regulators of Th1 and Th17 activities, from iDCs stimulated with different toll-like receptor (TLR) agonists in metalloid-free medium. Such As(III)-exposed DCs also exhibit reduced mRNA levels of IL12A and/or IL12B genes when activated with TLR agonists. Finally, differentiation of monocytes with non-cytotoxic concentrations of As(III) subsequently reduces the ability of activated DCs to stimulate the release of interferon-γ and IL-17 from Th cells. In conclusion, our results demonstrate that clinically relevant concentrations of inorganic arsenic markedly impair in vitro differentiation and functions of DCs, which may contribute to the putative beneficial effects of the metalloid towards inflammatory autoimmune diseases.
ISSN: 0041-008X

inserm-00813758
http://www.hal.inserm.fr/inserm-00813758
DOI : 10.1016/j.taap.2012.11.008
PUBMED : 23164666